(N)-Methanocarba 2,N6-disubstituted adenine nucleosides as highly potent and selective A3 adenosine receptor agonists
(N)-Methanocarba 2,N6-disubstituted adenine nucleosides as highly potent and selective A3 adenosine receptor agonists
复制标题
DOI：
10.1021/jm049580r
复制
发表时间：
2005-03-24
影响因子：
7.3
通讯作者：
Jacobson, KA
中科院分区：
文献类型：
--
作者：
Tchilibon, S;Joshi, BV;Jacobson, KA
通过核碱基前体与含有5 '-酯官能团的假糖环的Mitsunobu缩合反应，合成了一系列环约束的（N）-甲氨基甲酸-5'-糖醛酰胺2，N-6-二取代腺嘌呤核苷。在腺嘌呤环的适当官能化之后，将酯基转化为5 '-N-甲基酰胺。这些化合物，主要是2-氯取代的衍生物，在人腺苷受体（AR）的结合和功能测定中进行了测试，发现许多化合物是高度有效和选择性的A（3）AR激动剂。比较所选化合物与大鼠A（3）AR的结合，以评估它们在大鼠疾病模型中的可行性。N-6-（3-氯苄基）和N-6-（3-溴苄基）类似物在人A（3）AR处显示的Ki值分别为0.29和0.38 nM。观察到以下N-6衍生物的其它亚纳摩尔亲和力：2，5-二氯苄基、5-碘-2-甲氧基苄基、反式-2-苯基-1-环丙基和2，2-二苯基乙基。与A（3）AR相比，人A3 AR的选择性如下（倍数）：N-6-（2，2-二苯基乙基）类似物34（1900），N-6-（2，5-二甲氧基苄基）类似物26（1200）、N-6-甲氧基苄基类似物26（1200）。（2，5-二氯苄基）和N-6-（2-苯基-1-环丙基）类似物20和33（1000），以及N-6-（3-取代苄基）类似物17、18、28和29（700-900）。通常，与A（2A）和A（2B）AR相比，获得甚至更大的选择性比率。在10 μ M的浓度下，（N）-甲烷卡巴-5 ′-糖醛酰胺类似物对毛喉素刺激的腺苷酸环化酶有抑制作用，表明它是A（3）AR的完全激动剂。N-6-（2，2-二苯基乙基）衍生物是（N）-methanocarba-5 '-uronamide系列中的A（3）AR激动剂，尽管它是核糖系列中的拮抗剂.因此，许多先前已知的在9-核苷系列中增强A（3）AR亲和力的基团，包括那些降低内在功效的基团，可以适用于完全激动剂的（N）-甲烷卡巴核苷系列。
A series of ring-constrained (N)-methanocarba-5 '-uronamide 2,N-6-disubstituted adenine nucleosides have been synthesized via Mitsunobu condensation of the nucleobase precursor with a pseudosugar ring containing a 5 '-ester functionality. Following appropriate functionalization of the adenine ring, the ester group was converted to the 5 '-N-methylamide. The compounds, mainly 2-chloro-substituted derivatives, were tested in both binding and functional assays at human adenosine receptors (ARs), and many were found to be highly potent and selective A(3)AR agonists. Selected compounds were compared in binding to the rat A(3)AR to assess their viability for testing in rat disease models. The N-6-(3-chlorobenzyl) and N-6-(3-bromobenzyl) analogues displayed K-i values at the human A(3)AR of 0.29 and 0.38 nM, respectively. Other subnanomolar affinities were observed for the following N-6 derivatives: 2,5-dichlorobenzyl, 5-iodo-2-methoxybenzyl, trans-2-phenyl-1-cyclopropyl, and 2,2-diphenylethyl. Selectivity for the human A3AR in comparison to the A(3)AR was the following (fold): the N-6-(2,2-diphenylethyl) analogue 34 (1900), the N-6-(2,5-dimethoxybenzyl) analogue 26 (1200), the N-6-(2,5-dichlorobenzyl) and N-6-(2-phenyl-1-cyclopropyl) analogues 20 and 33 (1000), and the N-6-(3-substituted benzyl) analogues 17, 18, 28, and 29 (700-900). Typically, even greater selectivity ratios were obtained in comparison with the A(2A) and A(2B)ARs. The (N)-methanocarba-5 '-uronamide analogues were full agonists at the A(3)AR, as indicated by the inhibition of forskolin-stimluated adenylate cyclase at a concentration of 10 mu M. The N-6-(2,2-diphenylethyl) derivative was an A(3)AR agonist in the (N)-methanocarba-5 '-uronamide series, although it was an antagonist in the ribose series. Thus, many of the previously known groups that enhance A(3)AR affinity in the 9-riboside series, including those that reduce intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists.